Workshop 2: Metastasis and Angiogenesis
Cell-extracellular matrix interaction and the mechanical properties of cell nucleus have been demonstrated to play a fundamental role in cell movement across fibre networks and micro-channels. In the talk, we will describe several mathematical models dealing with such a problem, starting from modelling cell adhesion mechanics to the inclusion of influence of nucleus stiffness in the motion of cells.
An energetic approach is used in order to obtain a necessary condition for which cells enter cylindrical structures. The nucleus of the cell is treated either (i) as an elastic membrane surrounding a liquid droplet or (ii) as an incompressible elastic material with Neo-Hookean constitutive equation. The results obtained highlight the importance of the interplay between mechanical deformability of the nucleus and the capability of the cell to establish adhesive bonds.
Cell locomotion is essential for early development, angiogenesis, tissue regeneration, the immune response, and wound healing in multicellular organisms, and plays a very deleterious role in cancer metastasis in humans. Locomotion involves the detection and transduction of extracellular chemical and mechanical signals, integration of the signals into an intracellular signal, and the spatio-temporal control of the intracellular biochemical and mechanical responses that lead to force generation, morphological changes and directed movement. While many single-celled organisms use flagella or cilia to swim, there are two basic modes of movement used by eukaryotic cells that lack such structures -- mesenchymal and amoeboid. The former, which can be characterized as `crawling' in fibroblasts or `gliding' in keratocytes, involves the extension of finger-like filopodia or pseudopodia and/or broad flat lamellipodia, whose protrusion is driven by actin polymerization at the leading edge. This mode dominates in cells such as fibroblasts when moving on a 2D substrate. In the amoeboid mode, which does not rely on strong adhesion, cells are more rounded and employ shape changes to move -- in effect 'jostling through the crowd' or `swimming'. Here force generation relies more heavily on actin bundles and on the control of myosin contractility. Leukocytes use this mode for movement through the extracellular matrix in the absence of adhesion sites, as does Dictyostelium discoideum when cells sort in the slug. However, recent experiments have shown that numerous cell types display enormous plasticity in locomotion in that they sense the mechanical properties of their environment and adjust the balance between the modes accordingly by altering the balance between parallel signal transduction pathways. Thus pure crawling and pure swimming are the extremes on a continuum of locomotion strategies, but many cells can sense their environment and use the most efficient strategy in a given context. We will discuss some of the mathematical and computational challenges that this diversity poses.
Anisotropic diffusion describes random walk with different diffusion rates in different directions. I will present a form of anisotropic diffusion which is called "fully" anisotropic. The fully anisotropic diffusion model does not obey a maximum principle and can even lead to singularity formation in infinite time.
I will derive this model from biological principles, analyse some of its behavior and show how it can be used to model glioma spread.
We investigate local and global existence, blowup criterion and long time behavior of classical solutions for a system derived from the Keller-Segel model describing chemotaxis. We study the existence and the nonlinear stability of large-amplitude traveling wave solutions to the system.
I will review our efforts to develop imaging, modeling and simulation tools for the study of angiogenesis. I will address the challenge of predictive simulations for Life Science applications and discuss a Bayesian uncertainty quantification and propagation framework that can help bridge experiments and simulations.
Formation of functionally adequate vascular networks by angiogenesis presents a problem in biological patterning. Generated without predetermined spatial patterns, networks must develop hierarchical tree-like structures for efficient convective transport over large distances, combined with dense space-filling meshes for short diffusion distances to every point in the tissue. Moreover, networks must be capable of restructuring in response to changing functional demands without interruption of blood flow. Here, theoretical simulations based on experimental data are used to demonstrate that this patterning problem can be solved through over-abundant stochastic generation of vessels in response to a growth factor generated in hypoxic tissue regions, in parallel with refinement by structural adaptation and pruning. Essential biological mechanisms for generation of adequate and efficient vascular patterns are identified and impairments in vascular properties resulting from defects in these mechanisms are predicted. The results provide a framework for understanding vascular network formation in normal or pathological conditions. With regard to tumor microcirculation, the simulations indicate possible factors leading to characteristic features including poor tissue oxygenation in the presence of adequate overall perfusion, and persistent instability of vessel structure and flow patterns.